Specific Aims Over the past 100 years we have acquired a comprehensive understanding of the neural mechanisms that regulate arterial pressure and peripheral resistance. In the past 20 years we have elucidated many cellular and molecular mechanisms that control sympathetic nerve activity. Much of this work has been driven by a lack of understanding of the mechanisms responsible for the development of essential hypertension. There is little doubt that augmented sympathetic nerve activity contributes to the pathogenesis of a variety of disease states including hypertension, heart failure, diabetes and panic disorders. We now have the capability to understand discrete molecular mechanisms responsible for altering sympathetic nerve activity in disease states. These mechanisms alter specific ion channel function and membrane properties in order to evoke sympatho-excitation. Current therapy for hypertension and heart failure, in large part, target the sympathetic nervous system and the renin- angiotensin II system (RAS). The effectiveness of these therapies is due to the intense activation of these systems. Unfortunately, these treatment paradigms have not changed for many years. In spite of the fact that new pharmacological therapies have slightly improved outcomes in recent years a large segment of patients are refractory to these treatments. This fact has prompted the scientific community to investigate new targets for pharmacological intervention and to look to device therapy for hypertension and heart failure. Examples of the latter are renal sympathetic nerve denervation and carotid sinus baroreceptor stimulation for treatment of patients with drug-resistant hypertension. Furthermore, the utilization of novel vectors for the delivery of proteins and genes to discrete areas of autonomic regulation and the advent of chronic recording techniques of physiological parameters has, more than any other time in history, provided the tools to discover new targets for therapy. An example of the latter is the demonstration by Lindley and coworkers (Circulation Research 94:402-409, 2004; Am. J. Physiol. 296:R1-R8. 2009) that transfection of the subfornical organ with superoxide dismutase in mice with heart failure, not only reduces sympathetic nerve activity but actually improves cardiac function. New nanoparticle delivery techniques can be utilized for targeted therapy to the central nervous system for the treatment of diseases characterized by sympathoexcitation. This American Physiological Society (APS) conference will focus on many of these mechanisms. Sessions will include the role of autocrine, paracrine and endocrine mediators of reflexes and areas of the central nervous system that are known to regulate sympathetic function (e.g. the hypothalamus and medulla). Symposia and poster presentations will focus on reactive oxidant stress, nitric oxide, angiotensin II, angiotensn (1-7), glutamate, GABA and the transcriptional and translational regulation of the receptors for many of these mediators. The areas of research to be discussed at this conference are pivotal to a translational approach in the treatment and management of primary autonomic disorders and to those evolving from cardiovascular and/or metabolic diseases. The melding of human, animal, cellular and molecular physiology will foster discussion of additional integrative approaches in this area of biomedicine. With the above in mind, the specific aims of the proposed conference are: 1. Bring together leaders in the field of autonomic cardiovascular physiology and pathophysiology for an intense discussion of the current research and therapy related to sympathoexcitation in a variety of disease states. 2. Provide a venue for junior investigators, graduate students and post-doctoral fellows to highlight their research in the form of oral and poster presentations. 3. Foster the generation of new ideas targeted to the translation of basic science into clinical therapies. 4. Establish new relationships between investigators in the area of autonomic regulation of cardiovascular function. 5. Provide an international forum in which underrepresented minorities can participate. PUBLIC HEALTH RELEVANCE: The purpose of this conference is to provide a scientific forum for the exchange of ideas and the presentation of the most recent data on the regulation of sympathetic nerve activity in health and disease. Sympathetic activation, while considered a physiologically relevant and important regulator of arterial pressure, blood flow and vascular resistance, is thought to contribute to pathology, if overactive. This is especially true in those conditions that require a high level of sympathetic tone to compensate for an abnormal cardiac output or where sympathetic nervous activity sustains arterial pressure in a range that is clearly detrimental to organ function. It is critical that a comprehensive understanding of the integrative mechanisms that take part in abnormal sympathetic function take place so that more rational therapy for these disorders can be developed. In this conference we will specifically focus on disorders that have been characterized as involving abnormalities in sympathetic regulation. The meeting will take an integrative approach to understanding sympathetic regulation and will incorporate genetic, molecular, cellular and whole animal approaches to the topics covered in this conference. There has never been an APS conference on this topic. The program will incorporate several topics related to sympathetic activation. These will include symposia related to central autocrine, paracrine and endocrine influences. New data on the ACE-ACE2 balance and central cellular signaling pathways will be covered. Oxidative stress is now thought to be part of normal cell signaling and in excess to contribute to activation of excitable cells and contribute to pathology. At least 1 symposium and several talks will be dedicated to sympathetic regulation in humans. These talks will include heart failure, hypertension, POTS, panic disorder and obesity/metabolic syndrome.